The invention relates generally to a method and apparatus for dissolution and transport of a pharmaceutical product in a fluid path system for use in magnetic resonance imaging (MRI) and analytical high-resolution NMR spectroscopy. MRI is a diagnostic technique that has become particularly attractive to physicians as it is non-invasive and does not involve exposing the patient under study to X-rays associated with other medical imaging techniques. Analytical high resolution NMR spectroscopy is routinely used in the determination of molecular structure.
MRI and NMR spectroscopy can, however, lack sensitivity due to the normally very low polarization of the nuclear spins of the contrast agents typically used. As such, a number of techniques exist to improve the polarization of nuclear spins while in the solid phase. These techniques are known as hyperpolarization techniques and lead to an increase in sensitivity. In hyperpolarization techniques, a sample of an imaging agent, for example 13C1-Pyruvate or another similar polarized imaging agent, is introduced or injected into the subject being imaged. As used herein, the term “polarize” refers to the modification of the physical properties of a material for further use in MRI. Further, as used herein, the term “hyperpolarized” refers to polarized at a level over that found at room temperature and at 1 Tesla, which is further described in U.S. Pat. No. 6,466,814.
In many instances, the imaging agent undergoes this hyperpolarization in an apparatus remote from its end use. The hyperpolarized material has a very short life span, and as such, the hyperpolarized material must be quickly transferred from its production source to its place of intended end use (i.e., injection into a patient) and transformed into a useable state. To accomplish this, the cryogenically frozen hyperpolarized material is dissolved into a dissolution medium for injection into the patient. Thus, as a part of a dynamic nuclear polarization (DNP) system, a means for dissolving the polarized sample within the polarizer must be included.
For a sample of polarized acid (e.g., pyruvic acid), it is necessary to use a dissolution medium to dissolve the sample and obtain a solution of polarized sodium salt (e.g., sodium pyruvate) suitable for in vivo injection. The dissolution medium typically is comprised of an aqueous solution including a base (e.g., sodium hydroxide) and a buffering agent (e.g., TRIS hydroxymethyl aminomethane (TRIS)) to dissolve the sample and control/reach a physiologically acceptable pH in the injectate, although the dissolution medium could also be in the form of water.
In the current methodology, a defined volume of dissolution medium containing sodium hydroxide, TRIS-buffer, and EDTA is pressurized with helium gas to a defined pressure in a titanium cylinder and heated to a defined temperature. When the dissolution process is started, the pressurized and heated solvent is released from the cylinder and guided by a continuous helium gas flow into contact with the polarized sample. This method suffers from the drawback that the dissolved sample is mixed with gas as it is ejected into the receiving container and therefore is not sterile for injection. This complicates the removal of the Electron Paramagnetic Agent (EPA) from the dissolved polarized sample and the sterile filtering of the injectate.
Additional problems can arise in existing methodologies that employ fluid path systems to dissolve the frozen sample. That is, one possible failure mode with the current fluid path system involves ensuring that the sample is completely dissolved by the dissolution medium. If the thermal energy, amount, and flow of the dissolution medium is insufficient to completely dissolve the sample, the system may freeze before the sample is dissolved, thus resulting in an ice plug completely blocking flow into and out of the fluid path system. A second failure mode is that the thermal energy transferred to the frozen sample is not sufficient to dissolve the entirety of the sample, resulting in some of the sample being left in a frozen/solid state after a defined volume of dissolution medium has been entered into the fluid path system. This failure to completely dissolve the sample affects the pH level and acid concentration of the injectate in the case of the sample being an acid. For example, pyruvate is a very reactive compound sensitive to both high and low pH (which may catalyze the pyruvate to react), and thus, it is important that the sample be completely dissolved to ensure a desired pH level in the injectate.
Another limitation of current methodology and devices used for dissolving pharmaceutical samples is the cost and complication associated with maintaining a sterile product. For pharmaceutical products, sterility assurance is essential and there can be no risk of contamination to the product. Current methods and devices require the sample to be handled and exposed to the environment. As such, any device in contact with the sample will have to be sterilized and sterility will have to be assured during the dissolution and transport of the sample.
Thus, a need therefore exists for a fluid path system that can rapidly and completely dissolve a frozen hyperpolarized material. It is also desirable that the dissolved material be fully displaced from its initial location to a final location in order to ensure suitable pH levels, acid concentration, and liquid state polarization in the injectable solution. The fluid path system should also provide maintained sterility during dissolution and transport of the material in a cost-effective and efficient manner.